Mood Disorders Emotion: acute, short-duration (minutes-hours) psychological response to a specific stimulus; shortduration Mood: moderate-duration emotional state

(hours-days); can be stimulus-independent (not necessarily tied to a specific stimulus) Trait: long duration (i.e. lifetime) stable, almost hard-wired bias in the way that we perceive and respond to the world Moods can be described with respect to two axes: valence (positive-negative) and intensity (high-low) Mood disorders: characterized by mood states that are so severe in the intensity - either negative or positive - and are of sufficiently long duration that they become maladaptive. both the magnitude of the mood state and its persistence, the length of time that people experience these intense states, that leads to impairment, dysfunction, and distress in people with mood disorders. Two major classes of mood disorders: Unipolar depressive disorders (e.g. Major Depressive Disorder; MDD) and Bipolar Disorder Two hallmark symptoms of MDD are dysphoria, the presence of abnormally high levels of negative mood, and anhedonia, abnormally low levels of positive mood. Bipolar Disorder: defining symptom of bipolar disorder is the presence of mania - excessively high levels of positive mood. In bipolar disorder, a patients mood state typically alternates between manic states and depressive - that is, anhedonic or dysphoric - states. MDD: Most common mood disorder (16% lifetime prevalence; 7% 1 year prevalence) 2:1 sex difference (women>men) KNOW DSM CRITERIA Course of illness: Single-episode vs. recurrent o SPECIFIERS ! Atypical features high levels of anxiety shows mood reactivity - meaning that these patients can actually respond to positive life events with a change in mood increased sensitivity to interpersonal rejection Patients with atypical features also tend to over-eat and gain a significant amount of weight during their depressive episodes more common in women, associated with an earlier age of onset and increased risk for suicide ! Melancholic features very severe presentation of MDD near complete anhedonia - an almost total loss of any positive mood, of the ability to experience pleasure and respond to positive life events Severe dysphoria lot of physical symptoms - psychomotor agitation or retardation, changes in sleep - typically early morning insomnia - and significant loss of appetite most likely to experience persistent and inappropriate feelings of guilt

Dysthymia: Persistent, sub-threshold depressive symptoms even though the symptoms are less severe in dysthymia compared to MDD, the fact that they are so chronic, are experienced consistently for years at a time, makes the functional impairment in dysthymia equivalent to that seen in MDD typical duration of dysthymia is 4-5 years, but can last > 20 years suicide risk worse in patients with dysthymia compared to MDD double depression: a depressive episode in the midst of a period of dysthymia Depression is HUGELY comorbid with anxiety disorders (>= 60%) Etiology and Pathophysiology of MDD Early causal factors o Genetics: MDD is heritable (~40%) ! HPA-axis genes, monoamine (serotonin, dopamine) genes ! variants cause changes in the way that the brain responds to stress and to threat ! KNOW HPA STRESS PATHWAY, AND ROLES OF AMYGDALA AND HIPPOCAMPUS IN IT ! 5HTTLPR short allele: increases risk for MDD increases amygdala activation in response to threat increases cortisol responses to stress o Early life environment: linear relationship between the number of adverse events that one experiences - these are things like childhood abuse, neglect, sexual assault, significant household stress and dysfunction - and the degree of increased risk for MDD. ! early life abuse increases amygdala activation in response to threat ! Following an acute stress, people with abuse have significantly higher stress hormone levels than people with no abuse Adult causal factors - not just acute traumatic events early in life that can lead to depression, but also stress that occurs in adulthood, particularly if its chronic. Even a mild stressor can predispose risk, if it is sustained over time Gene-X-Environment interaction: know about the interaction between o life stress and 5HTTLPR, o early life abuse and CRHR1 o mother/peer-rearing and 5HTTLPR in monkeys o (genes load the gun on depression and environment pulls the trigger) Cognitive mechanisms: o Becks Cognitive Model: ! For Beck, people become depressed because they have acquired a negative schema about themselves and their world. These negative schemas are dysfunctional beliefs - rigid, extreme, and counterproductive, and everything that

Psychotic features delusions and hallucinations psychoses are often mood-congruent, meaning that the content of the delusions and hallucinations relates to their depressed mood longer episodes worst long-term prognosis Seasonal pattern Seasonal affective disorder

! !

happens to a depressed person is filtered through the distorted lense of this negative schema. Depressed people acquire such schemas through a loss of a parent, rejection by peers, bullying, criticism from teachers or parents, the depressive attitude of a parent or some other negative life event. These schemas can lie dormant, unconscious even, until some event, some situation, activates them. For example, when the person with such a schema encounters a situation that resembles the original conditions of the learned schema in some way, even remotely, the negative schemas of the person are activated, and they enter a cycle of negative automatic thoughts NEGATIVE COGNITIVE TRIAD Depressed people hold a negative view of themselves - this colors how they view the world. This dysfunctional belief about the world causes them to make inaccurate predictions about the future, which feeds back on the negative belief about oneself. This trifecta of negative belief is called the negative cognitive triad So: dysfunction beliefs about the self, world, and future. COGNITIVE ERRORS negative cognitive triad is supported by a series of cognitive biases or errors Dichotomous thinking Overgeneralization Arbitrary inference Full cognitive model works like this: You have some kind of bad early experience - say, that leads to the creation of a set of dysfunctional negative beliefs about yourself, the negative schemas So Some negative event happens - you make a bad joke in class, you spill a soda in the dining hall, someone you like doesnt smile at you as you pass them in the yard - and this activates that negative schema thats been festering since childhood The negative schema causes a person to make cognitive errors, which are like looking at the world through a distorted pair of glasses or looking at yourself in a funhouse mirror. The cognitive errors serve to reinforce the negative schema and they make it absolutely IMPOSSIBLE to see the event for what it is, which is just, you know, ONE isolated incident with no predictive power WHATSOEVER for how people think about you and for your future. But that one event, warped by the funhouse mirror of those cognitive distortions, takes on ABSOLUTELY HUGE significance. It becomes all the information that is needed to confirm that pre-existing negative schema about yourself. This chain of mutually reinforcing bad thoughts - this stinking thinking - sends a person into a black hole of hopeless despair. Cognitive Behavioral Therapy: basic tenet of cognitive approach to MOOD is that some event happens, the event triggers thoughts, the thoughts trigger feelings, and the feelings trigger actions. And the feelings and the actions then feedback and reinforce the thoughts. So: CBT is focused on changing the thoughts. KNOW THE FOUR BASIC STEPS OF CBT CBT is effective not just for MDD, but for a ton of other disorders

Meds: Know what MAOIs, TCAs and SSRIs do, and the side effects of each SSRIs work, but effects are only significant in people with severe MDD CBT and Meds about equally effective BUT: effects of CBT last after discontinuation of therapy, while effects of meds do not o So the take home message here is that antidepressants may work, but we know that if you take someone off of them, theyre pretty likely to relapse. We know that, if CBT works for you, and we take you off of CBT, youre not really likely to relapse. So CBT is more like a cure, while meds are more like a bandaid. IS DEPRESSION A DISORDER OF LOW SEROTONIN? WHAT IS THE EVIDENCE FOR? WHY MY THIS NOT ACTUALLY BE THE CASE?

Bipolar Disorder: Bipolar disorder is a disorder in which people alternate between depressive symptoms and mania. Mania is a state of hyper-elevated positive mood - people in a manic state experience a ton of elation and euphoria o Mania: o Euphoria o hyperactivity/decreased need for sleep o grandiosity o rapid, incoherent speech (pressed speech) o impulsivity (including hypersexuality, spending drugs) o irritability and aggression o Bipolar I: full manic episodes alternating with full depressive episodes o Bipolar II: hypomanic episodes - which are characterized by somewhat less severe symptoms than full manic episodes - alternating with full depressive episodes o Cyclothymic Disorder: much longer lasting episodes, but the symptoms are less severe. The manic or depressive mood states can last for years, but rarely reach fully florid mania or depression o Specifiers: o Psychotic o Seasonal o Rapid Cycling o Suicide 4x as common in bipolar vs. MDD Principles of Emotions: o Emotions can be classified according to valence (positive or negative) and arousal (high or low) KNOW HOW TO CLASSIFY DIFFERENT EMOTIONS (e.g. happy = positive valence, high arousal; shame = negative valence, low arousal) o 5 +/- 2 basic emotions: including sadness, anger, contempt, fear, disgust, surprise, joy o 3 components to emotions o Behavioral: emotions are action tendencies that motivate specific patterns of behavior o Cognitive: cognitive schemas guide our appraisals and attributions of events and people o Physiological: automatic physiological responses to environmental stimuli contribute to how we experience and interpret them Fear and anxiety: the emotional roots of the anxiety disorders o Fear: a core emotion thats shared by many animals. It involves an immediate reaction to some kind of imminent threat - a bear attack, or someone pulling a gun on you as you withdraw money from an ATM at night. o behavioral components of fear include a motivation to flee, or, as a last resort, to fight

o cognitive components of fear include content related to the threat of impending death (Im going to die) o physiological components of fear include a maxed-out redlining of the sympathetic nervous system, to prepare your body to either run like hell or fight like hell. o Anxiety: feelings of anxiety dont have to do with the present at all, but are entirely oriented toward predicting or preparing for something bad thats going to happen in the future. Anxiety is really all about anticipation - the anticipation of some bad thing looming on the horizon that is in some way out of your control. o adaptive evolutionary value of anxiety may be that this anticipatory response actually helps you to plan and prepare for some potential threat. o At the behavioral level, anxiety primes an avoidance response. o At the cognitive level, anxiety is characterized by a pre-occupation with the anxiogenic stimulus - whatever the thing is thats producing the anxious state. The cognitive state is one of worry, of rumination, of dread about the future. o Physiologically, anxiety is characterized by a marked activation of the HPA stress pathway that we talked about a few lectures back, and this produces a physiological state of hyper-arousal. o Anxiety disorders: cases in which, in some way or another, in some form or another, this anxiety response takes on a chronic pathological dimension that causes subjective distress and impairment. The specific anxiety disorders that well be talking about include. o High levels of comorbidity among all of the anxiety disorders. Which, you know, isnt really all that surprising given that all of these disorders are fundamentally just different expressions of the same basic psychopathology (anxiety). o Anxiety disorders as a class show high levels of comorbidity with a range of other disorders - most prominently major depression - as we discussed in our mood disorders section, but also with substance abuse. o At their core, all of these disorders are linked by a particular personality trait, which is sometimes called neuroticism the predisposition to experience negative mood states and respond to threat in an exaggerated manner. ! Etiology: genetics Like depression, anxiety and substance abuse are heritable, and twin studies have shown that some of the same genetic risk factors that predispose the development of depression also predispose the development of anxiety disorders and substance abuse. Whats likely happening here is that the pleiotropic effects of genetic factors increase risk for a broad domain of psychopathology - and the particular domain that were talking about here is the domain of negative affect. You have genetic factors that arent specifically associated with any one disorder, but instead make you more likely to experience negative affect, which we can see as higher levels of this neuroticism trait. And people with high levels of neuroticism are going to be more likely to develop all three of these disorders, which is the reason why we see such high comorbidity between them. Genetic variants in both the HPA stress pathway and in genes that encode aspects of serotonin, dopamine, and norepinephrine signaling all predispose high levels of neuroticism and the development of anxiety disorders. This gives us some potential insight into the pathophysiology of anxiety ! Pathophysiology: Stress

Involvement of HPA-axis genes suggests that individuals with high levels of neuroticism and anxiety show alterations in stress hormone levels, and we see that this is true. o people with high neuroticism scores have higher levels of cortisol upon awakening the people with low levels of neuroticism o people with high neuroticism scores show a much stronger cortisol response when theyre given a drug that artificially raises cortisol levels, compared to people with low neuroticism scores Altogether, this is consistent with the idea that there is something dysfunctional with the way that the body handles stress in people with high levels of neuroticism, this trait marker for anxiety disorders. we see many of the same patterns of altered stress hormone function in people who actually meet criteria for anxiety disorders. o we see the same pattern of altered morning cortisol levels in people with current anxiety disorders, either compared to people whose anxiety disorder has gone into remission or compared to controls. o people who are actively experiencing a panic attack have much higher levels of cortisol compared to when theyre not acutely experiencing a panic episode When we give the rat a drug that blocks the function of CRH corticotropin releasing hormone - the thing thats secreted by the hypothalamus and which causes the adrenal glands to release cortisol - they dont get as anxious. o We see a very significant anxiolytic effect - that is, an anxiety reducing effect - of interfering with the ability of CRH to do its job. In rats at least. What does this suggest about human targets? We also see hyper-active amygdala function in the anxiety disorders. This is particularly cool in that we see very similar patterns amygdala hyperactivity across different specific anxiety disorders, suggesting that this pattern of brain activity underlies something core and common to the experience of anxiety And people who do not meet criteria for anxiety disorders, but do show high neuroticism scores, also show over-activation of the amygdala This overactivation of the amygdala may be due to decreased top-down regulatory control over amygdala function by prefrontal cortex. o Specific Anxiety Disorders (overview) ! Generalized anxiety disorder (GAD): involves a diffuse feeling of worry or anxiety about many potential future threats the anxiety isnt targeted to one specific thing. ! Obsessive-compulsive disorder (OCD): people experience anxiety in response to a barrage of intrusive thoughts or mental images, and feel compelled to engage in ritualistic behavior to alleviate their anxiety ! Specific phobia: people experience anxiety about the possibility of encountering some phobic object or situation - like snakes or flying or the number 13 - and then fear and panic if and when they actually do encounter that feared thing ! Social phobia: phobic object or situation is actually, people; or really, negative social evaluation by people ! panic-disorder: more a disorder of fear, but shares many of the symptoms and neurobiology of the anxiety disorders GAD: often considered the "basic" or prototypical anxiety disorder o People with GAD have an intense, wide-ranging, and fundamentally

o o o

unfocused anxiety, a near-constant state of worry. They are constantly tense and uneasy, always on the look out of signs of threat in their world. They often fall into a black hole of worry when they need to make a decision about something - they try and predict every possible outcome, every possible ramification of every single choice option, and second-guess themselves to the point of madness, ruminating endlessly about their decision. A lot of avoidance behaviors in folks with GAD, things like procrastination - putting off decisions, putting off activities where they are uncertain about the outcome. We call this aggregate clinical picture anxious apprehension. It is the core, the absolute essence of GAD, and shows up in other anxiety disorders as well Muscle tension is the most pronounced physical symptom in GAD and the presence of this symptom seems to differentiate it from anxiety disorders with a panic component. The presence of fatigue is another distinguishing feature of GAD vs. panic. ! physical symptoms - muscle tension and fatigue - that most commonly bring people to the clinic, rather than the subjective distress that arises from their anxious apprehension. Cognitive mechanisms and dysfunctions ! Uncertainty intolerance: People with GAD experience their life as unpredictable and out of control. This is likely a function of the fact that all of our lives are, in fact, fundamentally unpredictable and out of our control, but this uncertainty is extremely aversive to people with GAD, and the negative affect engendered by the normal uncertainty of life magnifies that sense of unpredictability. people with GAD are intolerant of uncertainty, and in that light we can view many of their dysfunctional behaviors - like obsessive rumination and checking as desperate attempts to introduce some measure of control, some measure of certainty, some measure of PREDICTABILITY into a life that feels very UNPREDICTABLE and OUT OF CONTROL. ! Threat hypervigilance: an extreme sensitivity to cues for threat in the environment. People with GAD are always on the look out for things that are dangerous and harmful, always scanning the environment for threats - and we call this threat hypervigilance. In the lab, threat hypervigilance shows up as an attentional bias toward threat cues. Potentially threatening things are like attentional magnets to people with GAD. And you can measure this attentional bias toward threat in people with GAD by looking at their reaction times and eye movements when theyre asked to view and respond to matched pairs of emotional stimuli e.g., a threatening angry face, and a neutral face. o When you look at their eye-movements, its clear that theyre much quicker to shift their gaze

towards a threatening cue, like an angry face, and much slower to move their gaze away from it. This is unlike both controls or patients with MDD, who are generally quicker to shift their attention away from threat. o Behaviorally, theyre much quicker to respond to a cue thats in the same spatial location as a threatening face, suggesting that that threat cues have something like a magnetic property in people with GAD - their attention is more easily attracted to threat, and their attention remains focused on the place where the threat occurred, even after the threat itself is gone. Panic Disorder: o panic attacks describe an acute episode of extreme fear that occurs in the absence of any actual threat. o KNOW SYMPTOMS OF PANIC ATTACK o When a person experiences repeated, unexpected panic attacks, and begins to develop extreme anxiety about the mere possibility of having one, we consider this to be a chronic panic disorder o With agoraphobia: Panic disorder comes in two flavors - with and without agoraphobia, which is the fear of certain specific places or situations. These feared contexts are typically situations where a person has previously experienced a panic attack. For people with panic disorder plus agoraphobia is that their world becomes smaller and smaller and smaller, as more and more places become off limits due to their anxiety about having a panic attack in those places Specific phobias: o irrational fears of a specific object or situation o Most commonly observed phobias break down into about 6 or 7 categories - illness and injury; storms; specific animals; fear of open spaces; fear of death; fear of crowds; and fear of heights. o people who have these phobias recognize that their fear is unreasonable, but nevertheless have excessive responses to their phobic objects and go to great ends to avoid them. o How phobias develop: ! 1) through direct experience - where a bad experience with a specific phobic object or in a specific phobic context triggers a persistent and long-lasting phobia of that object or context ! 2) by experiencing a panic attack in a specific context or in proximity to a specific phobic object ! 3) we can learn phobias indirectly, by observing someone else - typically a parent or caregiver - experience a strong fear response to a phobic object or context Social phobia: o can be considered a severe or pathological form of shyness. o Similar to specific phobia, we see the same kind of avoidance behaviors around the phobic context, but in this case the phobic context is other people. In particular, the fear tends to revolve around the idea that other people will scrutinize them, will judge them harshly

o So: the specific content of the phobia is a fear of negative social evaluation o Infants as young as 4 months old can be evaluated for a trait called behavioral inhibition - these kids become more agitated and cry more frequently than their peers, and the presence of this trait early on is known to be a risk factor for the development of adult social phobia. OCD o Obsessive compulsive disorder or OCD is similar in many ways to the other anxiety disorders, with one key difference. With the anxiety disorders that weve seen up to now, anxiety is engendered by some kind of external stimulus. The threat lies in the world - be it people or snakes or work or school - the danger is on the outside. Not so with OCD. For people with obsessive compulsive disorder, the threat lies in their mind, in the form of obsessions. o OBSESSIONS: intrusive thoughts, impulses, images, or urges that people with OCD experience as incredibly disturbing an uncontrollable. Its these obsessions that are the source of anxiety in OCD, the threat. o COMPULSIONS: repetitive, ritualistic behaviors - compulsions that have the goal of reducing the anxiety associated with those incredibly intrusive obsessive thoughts. ! Typical obsessions Harming Contamination/disease Inappropriate behavior Safety/Order Obsessions and related compulsions break down into about 4 categories o Symmetry/neatness o Forbidden thoughts/actions o Cleaning/contamination o Hoarding o KNOW ASSOCIATED OBSESSIONS AND COMPULSIONS FOR EACH CATEGORY o Differences between OCD and other anxiety disorders, and implications for pathophysiology: ! In the other anxiety disorders, you see profound changes in corticolimbic circuitry - the amygdala and aspects of the prefrontal cortex - that we know are really important for regulating emotional arousal in response to external threats. The fact that the amygdala is relatively out of control, and the response of the amygdala inadequately regulated by prefrontal cortex, likely accounts for a good deal of the threat hypervigilance we see in anxiety disorders ! ith OCD though, whats out of control isnt the response to the external world. Its internal impulses and urges and thoughts that are poorly regulated. And theres another important feature of OCD that distinguishes it from the other anxiety disorders - the presence of a stereotyped set of ritualistic behaviors that are immediately triggered by the

presence of these internally generated impulses, urges and thoughts. And how does this behavior come about in the first place? Compulsions arise because they relieve anxiety. So people with OCD learn that when they do this very specific thing, they get some relief from anxiety, relief from pain - a negative or aversive stimulus is removed. In this way, we can think of compulsions as the product of a dysfunctional learning process - stimulus, response; stimulus, response, stimulus-response. In particular, its a kind of learning that we can call habit learning, whereby a person develops a specific behavior routine thats automatically activated in response to a particular stimulus, or in response to a particular context. This kind of learning can be really useful inasmuch as its efficient - you dont have to think about performing a habit. But habits are problematic because they lead to inflexible, stimulusdriven behavior. They are very hard to over-ride once learned. when we look at the brains of people with OCD we see why this might be the case. OCD is associated with a disruption within a brain circuit thats really important for behavior flexibility. We call this a corticostriatal circuit because its comprised of the ventromedial prefrontal cortex and the striatum. This circuit is really important for learning associations between actions patterns and outcomes - especially when these associations involve motivationally salient outcomes like rewards and punishment - and its also absolutely necessary for updating these associations to permit a goal-directed over-ride of automatic habits. this disruption in corticostriatal circuitry in people with OCD is one reason why they are really good at forming these compulsive habit behaviors, and really bad at exerting goal directed, willfull control over the performance of a compulsive behavior once its triggered So we can think of this as an imbalance between goal-directed behavior and habit learning in people with OCD, where the habit learning wins. Addiction Addiction is a chronic, relapsing disease that is characterized by compulsive drug seeking and use, despite harmful consequences approximately 9% of Americans meet the DSM-IV criteria for addiction every year counting costs like treatment, incarceration,lost productivity and crime addiction accounts for a total ESTIMATED cost to this country of around a half a trillion dollars.

o Three primary components: o compulsion to seek and take a drug of abuse o loss of control in limiting drug intake o emergence of a negative emotional state when access to the drug is limited o Stages of addiction: o early stage: people take these drugs specifically because they like the pleasure that they provide. This is a goal driven act, a decision to engage in a behavior because of the specific outcome of that behavior. We call this activity drug taking. o late stage: over time, in some people, because of the way that these drugs change the way that the brain works, a shift happens. People stop taking drugs as the result of a goal-directed choice. Drug use becomes an inflexible, compulsive habit that persists even in the face of significant negative consequences. Exactly like the compulsive habits in OCD, addicted people cannot will themselves out of drug use, cannot talk themselves out of drug use, and cannot easily use feedback that they get about the results of drug use to change or guide their behavior. o This compulsive drug seeking that persists even after significant, mounting, and meaningful negative consequences - like the loss of a job, ones family, and ones health - is really the hallmark of addiction. o SO: ! Early stage: goal-driven, pleasure-based drug taking ! Late stage: habit-driven, compulsive, drug seeking o Know the DSM operationalization of addiction: o Tolerance: increasing amounts of drug required to reach intoxication o Withdrawal symptoms upon drug discontinuation o Larger amounts of drug taken than were intended o Persistent desire and unsuccessful attempts to cut drug use o Great deal of time spent getting drug, using it, recovering from it o Important social, occupational, recreational activities given up/reduced because of substance abuse o Substance use continued despite knowledge of having persistent/recurrent physical or psychological problems caused/exacerbated by the drug o Most people who use drugs dont become addicted: only a minority of people who try drugs of abuse progress from the early stage to the late stage. Whats so special about the people that do? o Genetics: genetic factors account for who is susceptible to convert from drug use to addiction and who does not o Environment: childhood maltreatment and stress ! important for determining who uses drugs in the first place, who transitions to addiction, and who relapses (i.e. once sober/clean) o Pathophysiology: ! addiction is a disease of reward and motivation ! Drugs act as reinforcers - they act on very old brain systems that are crucial for motivating an organism to engage in survival-critical behaviors like eating, drinking, and having sex. A key part of the transition to addiction is that these drugs rewire brain circuits for motivation in such a manner that the brain learns that the acquisition of the drug is a survival critical function. Drugs shape motivational circuitry to increase the drive, the urgency, to engage in drug seeking behaviors. ! They do this by acting on the mesolimbic dopamine reward system. All drugs of abuse cause the release of dopamine within the nucleus accumbens, a brain region located within the ventral striatum

! !

This action appears to be essential for their reinforcing properties, and is a key component of their ability to motivate behavior. So what does dopamine do? Dopamine is a really misunderstood neurotransmitter. People often think that DA is involved in the subjective feeling of pleasure that one feels on being exposed to a reward, but this isnt really the case. Rather, DA is most important for motivating behavior to obtain rewards, and so when DA is released in the nucleus accumbens when one sees a reward-predicting cue this is really a chemical signal that organizes or drives behavior to make sure that the reward is obtained